Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1

• Published in: The Journal of physiology 2014-01, Vol.592 (1), p.103-123
• Main Authors: Nagode, Daniel A., Tang, Ai‐Hui, Yang, Kun, Alger, Bradley E.
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animals; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - physiology; Cannabinoids - pharmacology; Cholecystokinin - genetics; Cholecystokinin - metabolism; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Cholinergic Neurons - physiology; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Inhibitory Postsynaptic Potentials; Interneurons - drug effects; Interneurons - metabolism; Interneurons - physiology; Mice; Neuroscience: Cellular/Molecular; Opsins - genetics; Opsins - metabolism; Optogenetics; Parvalbumins - genetics; Parvalbumins - metabolism; Theta Rhythm
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2013.257428

Key points •  Low‐frequency (4–14 Hz, ‘theta’) neuronal oscillations are essential for various animal behaviours, and are strongly influenced by inhibitory neuronal activity, although the interneurons responsible for such activity are not known. •  We used optogenetic methods to identify the generators of cholinergically activated, theta‐frequency inhibitory postsynaptic currents (IPSCs) in mouse CA1 hippocampus. •  Rhythmic IPSCs are driven by the activation of muscarinic acetylcholine receptors (mAChRs) via mAChR agonist application or ACh release from cholinergic axons. •  The output of parvalbumin (PV)‐expressing interneurons was prevented optogenetically or pharmacologically without affecting mAChR‐dependent oscillatory IPSCs. Instead, these IPSCs were blocked by inhibiting interneurons that express glutamic acid decarboxylase 2 (Gad2) and cannabinoid receptors, primarily the cholecystokinin (CCK)‐expressing cells. •  Theta‐frequency IPSCs were also inhibited by a μ‐opioid receptor agonist, suggesting that, in addition to being a potential substrate for the generation of behaviourally important rhythms, the same interneurons are a site of convergence of the cannabinoid and opioid neuromodulatory systems.   Neuronal electrical oscillations in the theta (4–14 Hz) and gamma (30–80 Hz) ranges are necessary for the performance of certain animal behaviours and cognitive processes. Perisomatic GABAergic inhibition is prominently involved in cortical oscillations driven by ACh release from septal cholinergic afferents. In neocortex and hippocampal CA3 regions, parvalbumin (PV)‐expressing basket cells, activated by ACh and glutamatergic agonists, largely mediate oscillations. However, in CA1 hippocampus in vitro, cholinergic agonists or the optogenetic release of endogenous ACh from septal afferents induces rhythmic, theta‐frequency inhibitory postsynaptic currents (IPSCs) in pyramidal cells, even with glutamatergic transmission blocked. The IPSCs are regulated by exogenous and endogenous cannabinoids, suggesting that they arise from type 1 cannabinoid receptor‐expressing (CB1R+) interneurons – mainly cholecystokinin (CCK)‐expressing cells. Nevertheless, an occult contribution of PV‐expressing interneurons to these rhythms remained conceivable. Here, we directly test this hypothesis by selectively silencing CA1 PV‐expressing cells optogenetically with halorhodopsin or archaerhodopsin. However, this had no effect on theta‐frequency IPSC rhythms induced by carba